Cancer can be caused by a wide variety of genetic abnormalities, such as hereditary or non-hereditary mutations. However, many of the known genetic causes of cancer are caused by mutations in or overexpression of genes that belong to a class encoding proteins having similar functional characteristics. For example, cell cycle regulatory genes are a class of genes that have been found to be mutated or differentially expressed in some cancers.
Cell cycle regulatory genes include genes that encode for cyclins and cyclin-dependent kinases (CDKs). Different cyclins are expressed and degraded at different stages of the eukaryotic cell cycle. Cyclins are positive cell cycle regulators, as they bind and activate CDKs, which contribute to the progression of the cell cycle from one stage of the cell cycle to the next stage of the cell cycle. CDK inhibitors are negative cell cycle regulators that bind cyclin-CDK complexes and inhibit the activity of CDKs in the cyclin-CDK complexes.
One example of a CDK inhibitor gene is the p27 gene, which encodes p27 protein, also known as p27Kip1. The p27 protein inhibits the activity of CDKs that are involved in the G1 to S phase transition of the cell cycle, contributing to G1 arrest of the cell cycle and prevention of unregulated, abnormal cell division.
While mutations in the p27 gene have not been found to date in human tumors, the level of p27 protein in many human tumors has been found to be below the level of p27 protein typically found in healthy human tissue. As the level of p27 protein in cells is regulated primarily at the post-transcriptional level, it is believed that factors that contribute to the degradation of p27 protein play a key role in regulating the level of p27 protein in cells.
HER-2 protein is a protein that is believed to be involved in the degradation of p27 protein. An inverse relationship between the amount of HER-2 protein and the amount of p27 protein has been found in primary breast tumor samples. Overexpression of HER-2 protein in a breast cancer cell line resulted in reduced levels of p27 protein in the cell line (Yang, et al., Journal of Biological Chemistry 275:24735-24739 (2000)).
Methods of using the HER-2 gene or protein in breast cancer diagnostics and therapeutic agents for breast cancer have been proposed (see, e.g., U.S. Pat. No. 6,251,601 and Herceptin® antibody, available from Genentech, San Francisco, Calif.). However, overexpression of HER-2 protein via gene amplification of the HER-2 gene has been found to date in only approximately 25% of breast cancer patients. Furthermore, one study has shown that less than half of the HER-2 overexpressing breast cancer patients in the study responded to HER-2 antibody-based treatment (Vogel, et al., Journal of Clinical Oncology 20: 719-726 (2002); Baselga J et al., Seminars in Oncology, Vol 26(4): Suppl. 12 pp 78-83, 1999; Slamon D. J., et al., The New England Journal of Medicine, Vol 344 pp 783-792, 2001; Vogel C. L et al., Journal of Clinical Oncology, Vol 20, pp 719-726, 2002).
In vitro studies of JAB1 protein (also referred to as CSN5 or p38JAB1) demonstrate that JAB1 protein contributes to the degradation of p27 protein, as overexpression of JAB1 protein in cultured cell lines resulted in decreased levels of p27 protein in the cell lines (see, Tomoda, et al., Nature 398:160-165 (1999), and Tomoda, et al., Journal of Biological Chemistry 277:2302-2310 (2002)).
To date, JAB1 protein has been studied in several types of human cancer (see, Tsuchida, et al., Jpn J Cancer Res. 93:1000-6 (2002), and Shen, et al., International Journal of Oncology 17:749-754 (2000)). In one study, it was found that the amount of JAB1 protein was inversely related to the amount of p27 protein in tumors of ovarian carcinomas; however, no correlation was found between JAB1 protein overexpression and the histological characteristics of the tumors, such as the stage of the patients' cancer and the grade of the tumors (Sui, et al., Clinical Cancer Research 7:4130-4135 (2001)). Shen et al. (2000) describe high levels of p27 in neuroblastomas, particularly in differentiated tumors. Localization of subcellular JAB1 expression was determined to be in both the nucleus and cytoplasm of undifferentiated and differentiating tumors, whereas predominantly nuclear localization was identified in differentiated tumor cells.
In another study, no difference was found between JAB1 protein levels in human pituitary tumors, such as corticotroph tumors or other pituitary adenomas, compared to normal pituitary tissue; however, a small but significant increase in JAB1 protein was detected in pituitary carcinomas compared to normal pituitary tissue (Korbonits, et al., Journal of Clinical Endocrinology and Metabolism 87:2635-2649 (2002)). The same study also examined p27 protein levels in human pituitary tumors. Low p27 protein levels were found in corticotroph adenomas and pituitary carcinomas. The study concluded that the low p27 protein levels found in corticotroph adenomas were not caused by JAB1 overexpression, as JAB1 overexpression was not found in corticotroph adenomas. Thus, it appears that JAB1 protein levels are elevated in some tumors in certain tissues, but are not elevated in tumors in other tissues, and that low p27 protein levels in cancer cells are not always correlated with a high level of JAB1 protein expression.
Previous studies have found that low p27 protein levels in breast tumors are often correlated with a poor prognosis and survival rate (Catzavelos, et al. (1997) Nat. Med. 3:227-230, Porter, et al. (1997) Nat. Med. 3:222-225). However, the investigations described herein indicate that JAB1 protein expression is frequently found in breast tumor cells and that JAB1 protein expression is prognostic of a lower survival rate and a lower progression-free survival rate. As discussed above, embodiments described herein also indicate that JAB1 protein levels and p27 protein levels are often inversely related in breast carcinomas and in T-cell lymphoma.
EP0856582 describes an inhibitor of the transcription factor activator protein-1 and a DNA encoding same. In particular embodiments, the inhibitor is the exportin protein.
United States Patent Application Publications US 20020156012; US 20030166243; and US 20030153097 relate to the peptidase activity of the JAB subunit or JAM domain. Compositions comprising the JAM domain are disclosed therein, and in some embodiments they are utilized to screen for agents that affect the peptidase activity. These agents may be further utilized for rational drug design. In specific embodiments, a screen entails in part the contact of a target protein to a JAB subunit, and there is also provided amelioration of a pathologic condition by modulating the activity and agents directed thereto.
United States Patent Application Publication US 20030148954 describes agents for modulating AP-1 mediated gene expression, such as those comprising an internalization moiety and a peptide from the intracellular domain of Notch-1 or an analog or peptidomimetic thereof.
There remains a need for biological markers that can be used as a basis for diagnosing and prognosticating different types of cancer, as well as a need for therapeutic agents for treating such cancers.